Mechanisms contributing to the age at onset of temporal lobe epilepsy due to hippocampal sclerosis.

Temporal lobe epilepsy (TLE) secondary to hippocampal sclerosis (HS) is a common cause of drug-resistant epilepsy. HS is characterized by neuronal loss in selected hippocampal subfields and gliosis. Age at epilepsy onset (AEO) critically influences disease severity and treatment response. We compared early AEO (<10 years) and late AEO (>11 years) in hippocampi from patients undergoing surgery for HS (n = 30). HS hippocampi showed altered mitochondrial enzyme activities and membrane potential (vs controls). Early AEO showed reduced membrane potential and ATP and increased proton leak, whereas other activities did not differ significantly between early and late AEO. Altered proteomic profile of mitochondrial complexes, organization, and metabolic pathways was noted in early AEO. Astrocytic proteomics revealed altered markers of blood-brain barrier (BBB), apoptosis, and excitotoxicity in early AEO. Overexpression of aquaporins, BBB junction proteins, and ion channels suggests compensatory mechanisms in late AEO. Proteomics of hippocampal subfields revealed increased expression of antioxidant and synaptic proteins in dentate gyrus in late AEO, indicating neuroprotective mechanisms, whereas CA1 showed downregulation of glutamate receptors and mitochondrial proteins, consistent with neuronal death. Based on these results, we propose that early AEO-HS is associated with mitochondrial dysfunction, whereas non-mitochondrial factors are associated with late AEO-HS.